Using CD4 Percentage and Age to Optimize Pediatric

Antiretroviral Therapy Initiation

WHAT’S KNOWN ON THIS SUBJECT: In HIV-infected children, AUTHORS: Dwight E. Yin, MD, MPH,a,b,c Meredith G.
decisions to start antiretroviral therapy must weigh immunologic Warshaw, MSS, MA,d William C. Miller, MD, PhD, MPH,b,e
benefits against potential risks. Current guidelines recommend Hannah Castro, MSc,f Susan A. Fiscus, PhD,g Lynda M.
using CD4 percentage and age when deciding to start treatment. Harper, MSc,f Linda J. Harrison, MSc,d Nigel J. Klein,
MBBS,h Joanna Lewis, PhD,i Ann J. Melvin, MD, MPH,j
Population-level effects of these factors on immunologic recovery
Gareth Tudor-Williams, MD,k and Ross E. McKinney Jr, MD,a
are unknown.
on behalf of the PENPACT-1 (PENTA 9/PACTG 390) Study
Team
WHAT THIS STUDY ADDS: Starting antiretroviral therapy at higher aDivision of Infectious Diseases, Department of Pediatrics, Duke
CD4 percentages and younger ages maximizes potential for University Medical Center, Durham, North Carolina; bDepartment
immunologic recovery. However, not all benefits are sustained, of Epidemiology, Gillings School of Global Public Health, eDivision
and viral failure may occur. Our results help clinicians better Infectious Diseases, Department of Medicine, School of Medicine,
weigh immunologic benefits against viral failure risks. and gDepartment of Microbiology and Immunology, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina;
cDivision of Infectious Diseases, Department of Pediatrics,

Children’s Mercy Hospitals and Clinics, University of Missouri—

Kansas City, Kansas City, Missouri; dCenter for Biostatistics in
AIDS Research, Harvard School of Public Health, Boston,
abstract Massachusetts; fInfections Group, Medical Research Council
Clinical Trials Unit, hInfectious Diseases and Microbiology Unit,
BACKGROUND: Quantifying pediatric immunologic recovery by highly Institute of Child Health, and iInstitute of Child Health and
active antiretroviral therapy (HAART) initiation at different CD4 percent- CoMPLEX, University College London, London, United Kingdom;
jDivision of Pediatric Infectious Disease, Department of
age (CD4%) and age thresholds may inform decisions about timing of Pediatrics, Seattle Children’s Hospital, University of Washington,
treatment initiation. Seattle, Washington; and kSection of Pediatrics, Imperial College
London, London, United Kingdom
METHODS: HIV-1-infected, HAART-naive children in Europe and the Americas
KEY WORDS
were followed from 2002 through 2009 in PENPACT-1. Data from 162 ver-
child, HIV, immunologic, reconstitution, treatment failure
tically infected children, with at least World Health Organization “mild”
ABBREVIATIONS
immunosuppression and CD4% ,10th percentile, were analyzed for CD4%—CD4 percentage
improvement to a normal CD4% ($10th percentile) within 4 years after CDC—Centers for Disease Control and Prevention
HAART initiation. Data from 209 vertically infected children, regardless CI—confidence interval
DHHS—Department of Health and Human Services
of immune status, were analyzed for CD4% outcomes at 4 years and HAART—highly active antiretroviral therapy
viral failure within 4 years. LTFU—loss to follow-up
RCT—randomized controlled trial
RESULTS: Seventy-two percent of baseline immunosuppressed children
WHO—World Health Organization
recovered to normal within 4 years. Compared with “severe” immuno-
(Continued on last page)
suppression, more children with “mild” immunosuppression (differ-
ence 36%, 95% confidence interval [CI]: 22% to 49%) or “advanced”
immunosuppression (difference 20.8%, 95% CI: 5.8% to 35.9%) recov-
ered a normal CD4%. For each 5-year increase in baseline age, the
proportion of children achieving a normal CD4% declined by 19% (95%
CI: 11% to 27%). Combining baseline CD4% and age effects resulted in
.90% recovery when initiating HAART with “mild” immunosuppression
at any age or “advanced” immunosuppression at age ,3 years. Base-
line CD4% effects became greater with increasing age (P = .02). At 4
years, most immunologic benefits were still significant but diminished.
Viral failure was highest in infancy (56%) and adolescence (63%).
CONCLUSIONS: Initiating HAART at higher CD4% and younger ages max-
imizes potential for immunologic recovery. Guidelines should weigh immu-
nologic benefits against long-term risks. Pediatrics 2014;134:e1104–e1116

e1104 YIN et al
 ARTICLE

Determining optimal timing for initiation different CD4% and age thresholds on week 0); weeks 2, 4, 8, 12, 16, 24; and
of highly active antiretroviral therapy CD4% recovery. Our primary outcome then every 12 weeks until the last
(HAART) in children infected with HIV was the proportion of immunosup- enrollee reached 4 years of follow-up
remains a challenge. Globally in 2012, pressed children ever achieving a nor- (August 31, 2009). Full study details are
3.3 million children were living with HIV, mal CD4% ($10th percentile for age30) described elsewhere.31
and 210 000 children died due to AIDS.1 within 4 years of HAART initiation. Sec- Because previous PENPACT-1 analyses
Although HAART has improved long-term ondary outcomes were CD4% at 4 years found no significant differences among
survival,2 only 34% of eligible children after HAART initiation and the pro- randomized arms,31 we pooled participants
currently receive treatment.1 Treatment portion of children with a normal CD4% across arms. To minimize confounding
guidelines must consider public health at 4 years. The proportion of immuno- from unknown duration of infection,
implications for not only disease pro- suppressed children ever having a analyses were restricted to participants
gression,2,3 but also long-term compli- normal CD4% within 4 years of HAART who were infected vertically.
cations of drug toxicities,4 inadequate initiation reflects biological capacity
For the primary outcome (CD4% re-
adherence,5–7 resistance mutations,5 and for CD4% reconstitution. The CD4% and
covery within 4 years), data from ver-
cost-effectiveness. For HIV-infected infants, proportion of children normal at 4 years
tically infected children with at least
immediate HAART initiation is clearly reflect outcomes inclusive of initial
“mild” immunosuppression at baseline
needed, given its strong survival benefit,8,9 CD4% recovery, potential immunologic
by World Health Organization (WHO)
improved neurodevelopmental out- failure, and possible immune resto-
Immunologic Classification32 and CD4%
comes,10 faster growth recovery,11 and ration on a subsequent regimen.
,10th percentile for age30 were ana-
the population’s high mortality.12,13 How- lyzed to determine the proportion of
ever, for HIV-infected children presenting METHODS children who improved to normal
outside of infancy with minimal HIV- Participants CD4% ($10th percentile for age30) at
related symptoms, the clinical benefits any time within 4 years of follow-up. For
PENPACT-1 (Pediatric AIDS Clinical Trials
of early HAART initiation are unclear.14,15 secondary outcomes, data from all
Group 390/Paediatric European Network
Quantifying immunologic benefits of vertically infected children, regardless
for Treatment of AIDS 9)31 was an in-
treatment initiation at different CD4 of baseline immune status, were ana-
ternational, multicenter, phase 2/3, ran-
percentage (CD4%) and age thresholds lyzed for outcomes at 4 years after
domized, open-label, 2-by-2 factorial trial
may inform public health decisions re- HAART initiation: CD4% and proportion
enrolling HIV-1–infected children (aged
garding optimal HAART initiation timing. of children with normal CD4% (see
.30 days to ,18 years) in Europe,
Population-level immunologic effects of North America, and South America be- definitions in the next section).
HAART initiation at different CD4% and tween September 25, 2002, and Sep-
age combinations have been poorly tember 7, 2005. Eligible children had not Definitions
quantified because most previous stud- been treated with antiretrovirals or only To account for age-related variability
ies have only assessed associations. received antiretrovirals to reduce mother- of CD4%, we defined normal CD4% re-
HIV-infected children who initiate HAART to-child transmission (excluding single- covery based on data from healthy,
at lower CD4% reach lower peak CD4 dose nevirapine) for ,56 days and met urban-dwelling, pediatric patients in
levels,4,16–24 perhaps from persistent local indications for HAART. the United States.30 For the primary
effects of chronic immune activation.25,26 outcome, recovery to normal was de-
HAART initiation at younger ages is as- Procedures fined as 2 consecutive CD4% mea-
sociated with better immunologic re- At entry, children were randomly surements $10th percentile-for-age.
covery. 17–20,24,27,28 Some longitudinal assigned (1:1) in 2-by-2 factorial design: Time of recovery was defined as the
studies have quantified long-term CD4 (1) to start HAART with 2 nucleoside re- first of these CD4% measurements.
trajectories on HAART based on pre- verse transcriptase inhibitors plus either Participants lost to follow-up without
treatment CD4 and age, allowing pre- a protease inhibitor or nonnucleoside recovery were censored in Kaplan-Meier
dictions that are child-specific.24,29 reverse transcriptase inhibitor and (2) to analyses and counted as failures in re-
However, projected immunologic im- switch from first-line to second-line gression analyses.
pacts at population levels have not been HAART at viral load thresholds of either For secondary outcomes, CD4% at 4
established. 1000 copies/mL or 30 000 copies/mL. years was defined as the mean of CD4%
Our aim was to quantify population- CD4% and HIV RNA viral loads were measurements at weeks 192 and 204.
level impacts of HAART initiation at measured at randomization (baseline, At week 192, all participants were $3

PEDIATRICS Volume 134, Number 4, October 2014 e1105

years old, and CD4% 10th percentile- estimating age main effects were ad- review boards at Duke University and
for-age after 3 years old ranges be- justed for gender and race. Interactions University of North Carolina.
tween 28% to 31% without a consistent between immunologic classification and
age-related trend. Thus, the definition age were assessed and retained in RESULTS
of normal CD4% at 4 years was sim- models if P , .15. Hypothesis tests in Baseline Characteristics and
plified to be mean CD4% $30%.30,33 Poisson regression used score statistics; Overall Estimates
Participants missing 4-year CD4% mea- linear regression used likelihood ratio
PENPACT-1 enrolled 266 children infected
surements were excluded from second- tests. Statistical significance was defined
with HIV-1 from 68 centers in 13 coun-
ary outcome analyses. as 2-sided P , .05.
tries in Europe, North America, and
Baseline CD4% was categorized according Models were not adjusted for adher- South America; 263 were included in the
to a modified version of the WHO Immu- ence or viral failure because both vari- main trial analysis. For analysis of
nologic Classification for HIV-Associated ables are on the causal pathway to CD4% recovery within 4 years, 162 par-
Immunodeficiency.32 As this classification CD4% recovery.38 Adjustment for ad- ticipants with baseline immunosuppres-
switches to CD4 cell counts after age 5 herence or viral failure would control sion were included, and 209 qualified
years, we used the following immunode- for information unavailable to clinicians for analyses of CD4% status at 4 years
ficiency (CD4%) categories for subjects when making decisions about treat- (Supplemental Fig 4). The baseline char-
$5 years (same as ages 3 to ,5 years; ment initiation and would add bias to acteristics of all 209 vertically infected
see also the Centers for Disease Control estimates.40 However, we evaluated viral participants are shown in Table 1. At
and Prevention [CDC] HIV infection clas- failure to assess the degree to which baseline, WHO-staged CD4% was
sification systems34,35): “none/not sig- immunologic outcomes may be explained associated with age, race, and gender;
nificant” .25%, “mild” 20% to 25%, by poor viral control. Viral failure was marginally associated with continent
“advanced” 15 to ,20%, and “severe” defined as (1) failure to suppress HIV and CDC clinical stage; and not associated
,15%. RNA viral load to #400 copies/mL by week with growth parameters (weight-for-
24 of HAART or (2) after initial viral sup- age z score, height-for-age z score, and
Statistical Analysis pression, viral load .400 copies/mL for BMI-for-age z score) or baseline viral load.
Bivariate categorical analyses were 2 consecutive measurements, the first Age at HAART initiation was associated
performed by using Fisher’s exact test. occurring by week 192. Analyses used with race, continent, growth parameters,
Continuous variables were analyzed Cox models for testing associations baseline viral load, and baseline CD4%
by using linear regression. Trend line- and stratified proportional hazards but not associated with gender or CDC
arity was assessed by using polynomial models41 to estimate adjusted Kaplan- clinical stage.
expansion and restricted quadratic Meier failure probabilities. CD4% main Eighty-seven percent (182 of 209) of
splines with knots between quintiles. effect estimates were adjusted for age, participants had follow-up CD4% mea-
continent, and baseline viral load. Age surements at 4 years. LTFU was only
Recovery to normal CD4% within 4 years
main effect estimates were adjusted for associated with continent (Europe 5%,
was analyzed by Kaplan-Meier methods
continent. North America 27%, South America 10%;
with log-rank statistics and modified
Poisson regression on an additive scale Alosstofollow-up(LTFU)analysisevaluated P , .001). Correcting for LTFU did not
with Huber-White variance estimators bivariate relationships between baseline meaningfully alter study results (data
(additive Poisson).36,37 CD4% at 4 years characteristics and missing CD4% values not shown).
was analyzed by using multivariable at 4 years. To assess the potential influence Of 162 children with baseline immu-
linear regression while having normal of LTFU on results, sensitivity analyses nosuppression, the estimated proba-
CD4% at 4 years used additive Poisson corrected CD4% outcomes at 4 years for bility of achieving a normal CD4% within
regression. Models were constructed LTFU by using a method similar to direct 4 years was 72% (95% confidence in-
by using published literature and standardization (inverse-probability terval [CI]: 64% to 78%); mean CD4% at 4
hypothesis-driven a priori assumptions weighting methods).42 years was 30.9 (95% CI: 29.5 to 32.3); 56%
to guide statistical assumptions,38,39 Statistical analyses used SAS ver- of participants (95% CI: 48% to 64%) had
then reduced by backward elimination sion 9.3 (Cary, NC). This study is reg- normal CD4% at 4 years. Of 209 children
using P , .15 and .10% change-in- istered with International Standard with any baseline immune status, mean
estimate criteria. Models estimating Randomised Controlled Trial Number Reg- CD4% at 4 years was 32.8 (95% CI: 31.5 to
baseline CD4% main effects were ad- ister (ISRCTN73318385). The study pro- 34.2), with 64% (95% CI: 57% to 71%) of
justed for age, gender, and race. Models tocol was deemed exempt by institutional children having normal CD4% at 4 years.

e1106 YIN et al
 ARTICLE

TABLE 1 Characteristics of Children According to WHO Staged CD4% and Age at HAART Initiation
Variable WHO Immunologic Classification for HIV-Associated Immunodeficiency Age (y) at HAART
at HAART Initiation Initiation

Severe Advanced Mild None Total Pa Mean (SD) P

n 91 40 34 44 209
Age, n (%)
0–4 y 41 (41) 13 (13) 18 (18) 27 (27) 99 .07 2.0 (1.5) N/A
5–9 y 27 (39) 18 (26) 12 (17) 13 (19) 70 8.0 (2.2)
10–17 y 23 (58) 9 (23) 4 (10) 4 (10) 40 15.1 (1.5)
Age, y, M (SD) 6.3 (4.7) 7.0 (4.7) 4.9 (4.0) 4.2 (3.8) 5.8 (4.5) .01 5.8 (4.5)
Gender
Female, n (%) 35 (34) 18 (17) 25 (24) 25 (24) 103 .003 5.6 (4.5) .59
Male 56 (53) 22 (21) 9 (8) 19 (18) 106 6.0 (4.6)
Race, n (%)
Black, non-Hispanic 48 (42) 26 (23) 22 (19) 18 (16) 114 .04 6.8 (4.8) ,.001
White, non-Hispanic 12 (34) 5 (14) 3 (9) 15 (43) 35 3.2 (3.3)
Hispanic/other 31 (52) 9 (15) 9 (15) 11 (18) 60 5.5 (4.0)
Continent, n (%)
Europe 40 (43) 26 (28) 13 (14) 15 (16) 94 .05 5.0 (3.9) .002
North America 30 (48) 10 (16) 9 (14) 14 (22) 63 7.4 (5.5)
South America 21 (40) 4 (8) 12 (23) 15 (29) 52 5.2 (3.6)
CDC clinical stage, n (%)
N or A 41 (37) 24 (22) 24 (22) 22 (20) 111 .06 5.9 (4.8) .78
B or C 50 (51) 16 (16) 10 (10) 22 (22) 98 5.7 (4.1)
Treatment regimen, n (%)
NNRTI 46 (43) 16 (15) 22 (21) 22 (21) 106 N/Ab 5.3 (4.1) N/Ab
PI 45 (44) 24 (23) 12 (12) 22 (21) 103 6.3 (4.9)
Switching threshold, n (%)
1000 copies/mL 46 (44) 19 (18) 14 (13) 25 (24) 104 N/Ab 5.6 (4.5) N/Ab
30 000 copies/mL 45 (43) 21 (20) 20 (19) 19 (18) 105 6.0 (4.5)
z score, M (SD)
Weight for age 20.6 (1.6) 20.8 (1.2) 20.6 (1.1) 20.7 (1.5) 20.7 (1.4) .81 r = 0.32 ,.001
Height for age 21.0 (1.4) 21.0 (0.8) 20.8 (1.1) 20.8 (1.3) 20.9 (1.2) .81 r = 0.16 .02
BMI 20.0 (1.4) 20.4 (1.5) 20.2 (1.2) 20.2 (1.3) 20.2 (1.4) .59 r = 0.29 ,.001
Baseline viral load log10 copies/mL, M (SD) 5.2 (0.9) 5.1 (0.8) 4.8 (1.0) 5.0 (0.8) 5.1 (0.9) .31 r = –0.54 ,.001
Baseline CD4%, M (SD) 10.2 (5.7) 18.5 (3.8) 25.4 (4.9) 35.6 (7.1) 19.6 (11.4) N/A r = –0.44 ,.001
N/A, not applicable; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
a Comparisons used Fisher’s exact test for categorical variables and linear regression for continuous variables.
b P values are not reported because any differences were determined by randomization.

Baseline CD4% mal within 4 years (Fig 1), CD4% at 4 years (2) decrease in CD4% at 4 years of 2.9
CD4% recovery within 4 years was signif- (Table 2), and proportion of children nor- percentage points (95% CI: 1.4% to 4.3%;
icantly associated with WHO-staged base- mal at 4 years (Table 2). P , .001), and (3) reduction in pro-
line CD4% (Kaplan-Meier, P , .001; Fig 1). portion of children with a normal
In regression models, baseline CD4% was Age at HAART Initiation CD4% at 4 years of 7% (95% CI: –1% to
significantly associated with all three CD4% recovery within 4 years was sig- 16%; P = .08).
4-year CD4% outcomes: proportion of nificantly associated with age (Kaplan-
immune suppressed children ever re- Meier, P , .001; Fig 2). The association Combined Effects of Baseline CD4%
covering a normal CD4% within 4 years between age and CD4% recovery was and Age
(unadjusted P , .001, adjusted P , .001; approximately linear (by significance The interaction between baseline CD4%
Fig 1); CD4% at 4 years (unadjusted P , testing) for all three 4-year CD4% out- and age on the probability of ever re-
.001, adjusted P , .001; Table 2); and comes (Fig 3A–3C). In multivariable lin- covering a normal CD4% within 4 years
proportion of children normal at 4 years ear regressions adjusting for gender was statistically significant (unadjusted
(unadjusted P , .001, adjusted P , .001; and race, each 5-year increase in age at P = .009, adjusted P = .02; Table 3). This
Table 2). Compared with WHO “severe” HAART initiation had an estimated (1) interaction was synergistic: with increasing
immunosuppression, each increase in reduction of 19% in proportion of chil- age, baseline CD4% had a stronger ef-
baseline CD4% category had an increasing dren ever having a normal CD4% within fect on the capacity to recover a normal
trend in proportion of children ever nor- 4 years (95% CI: 11% to 27%; P , .001), CD4% within 4 years. However, interactions

PEDIATRICS Volume 134, Number 4, October 2014 e1107

 4 years. Twenty-nine (14%) failed to sup-
press to #400 copies/mL by week 24, and
53 (25%) suppressed but experienced vi-
ral rebound to .400 copies/mL. One
participant (0.5%) was LTFU before week
24. Viral failure was not associated
(Cox model, unadjusted P = .36, adjusted
P = .23) with baseline immunodeficiency
classification (adjusted Kaplan-Meier fail-
ure probability: “none” 32%, “mild” 54%,
“advanced” 44%, “severe” 40%). Viral
failure and age had a bimodal relation-
ship (Cox model, unadjusted P , .001,
adjusted P , .001) with peaks in infancy
and adolescence (adjusted Kaplan-Meier
failure probability: 0 to ,1 year 56%, 1 to
,3 years 34%, 3 to ,5 years 32%, 5 to
,8 years 24%, 8 to ,13 years 38%, 13
to , 18 years 63%; Fig 3D).

DISCUSSION
On the basis of these PENPACT-1 results,
initiating HAARTat healthier immunologic
stages and younger ages may have pro-
found impacts on immunologic recovery.
We suggest that HAART initiation when
children first have “mild” immunosup-
pression would result in almost all chil-
dren experiencing full CD4% recovery.
Similarly, HAART at younger ages would
yield high probabilities of immune re-
covery and may blunt negative effects of
“severe” immunosuppression. Although
FIGURE 1 not all children maintained immune re-
Cumulative proportion of children with CD4% recovery to normal versus weeks after HAART initiation, by covery (demonstrated by more attenuated
baseline WHO Immunodeficiency Classification (“mild,” “advanced,” “severe”). Primary outcome is
CD4% $10th percentile for age by week 192, marked by vertical dashed line. P value is from log-rank immunologic benefits at 4 years) most
statistic. CD4% outcomes at 4 years were still im-
proved in children starting HAART at
between baseline CD4% and age were “advanced” immunosuppression at healthier CD4 levels and younger ages. Our
not significant for CD4% at 4 years (un- age ,3 years. Adolescents with WHO results quantify the magnitude of these
adjusted P = .91; adjusted P = .91) or the “severe” immunosuppression had the effects on immunologic outcomes to help
proportion of children with normal CD4% lowest recovery probabilities, but the inform public health planning.
at 4 years (unadjusted P = .50, adjusted small sample size of adolescents made The PENPACT-1 data align with US De-
P = .59; Table 4). these estimates imprecise (Table 3). partment of Health and Human Services
A model including baseline CD4%, age, Trends were similar for CD4% out- (DHHS) pediatric HIV treatment guide-
gender, race, and a baseline CD4%-by- comes at 4 years (Table 4). lines.3,43 The DHHS recommends initiating
age interaction predicted .90% prob- HAART in all HIV-infected infants and
ability of CD4% recovery within 4 years Viral Failure any HIV-infected children with AIDS or
when initiating HAART with “mild” im- Of 209 vertically infected participants, most CDC Clinical Category B or C con-
munosuppression at any age or with 82 (39%) experienced viral failure within ditions; confirmed plasma HIV RNA levels

e1108 YIN et al
 ARTICLE

.100 000 copies/mL; aged 1 to ,3 years

Difference vs Severec
z scores and higher CD4% (33.2% vs

43% (29% to 57%)

30% (10% to 50%)
19% (0% to 38%)
with CD4 cell count ,1000 cells/mm3 or 24.8%).15 Neurodevelopmental scores
% (95% CI)

Reference
CD4% ,25%; ages 3 to ,5 years with CD4 were no different across arms.14 Links
count ,750 cells/mm3 or ,25%; or age among pretreatment CD4, age, and
$5 years with CD4 count ,500 cells/mm3 long-term CD4 recovery have been
Adjusteda

(with considerations for treating at established in literature.17–20,24 How-

Proportion Normal

90% (81% to 99%)

77% (60% to 94%)
66% (50% to 81%)
47% (36% to 58%)
higher CD4 levels).43 DHHS-recommended ever, our estimates allow the reader
% (95% CI)

CD4% and age treatment thresholds to quantify population-level immuno-

correspond to WHO immunodeficiency logic benefits of early versus delayed
classifications of “advanced” for ages treatment at combinations of CD4%
1 to ,3 years and “mild” for all age and age.
categories $3 years. If all children aged
Difference vs Severec

Adolescent recommendations are based

17% (–2% to 36%)
48% (35% to 61%)
32% (12% to 51%)

1 to ,13 years in PENPACT-1 had initi- primarily on adult data.44 Adult RCTs
% (95% CI)

Reference

ated HAART immediately after reaching found decreased AIDS progression or

DHHS-recommended CD4% and age treat- death with HAART in patients with acute
ment thresholds, we estimate .90% of opportunistic illnesses,45 CD4 ,200 cells/
Unadjusted
TABLE 2 CD4% Outcomes at 4 Years, Comparing WHO Immunodeficiency Classification None, Mild, Advanced Versus Severe Suppression

these children would have experienced mm3,46 or CD4 200 to ,350 cells/mm3.47
Adjusted for age, gender, and race. Mean CD4% and proportion normal are estimated at the covariate distribution of secondary outcomes subset (mean age 5.8 y).

CD4% recovery to normal within 4 years,

95% (87% to 100%)d

Adult cohort studies suggest that initi-

Proportion Normal

78% (62% to 93%)

63% (48% to 78%)
46% (35% to 57%)

and .80% would have had a normal

% (95% CI)

ating HAART at CD4 counts 350 to 500

CD4% at 4 years. cells/mm3 reduces HIV-related disease
Evidence supporting early treatment is progression but have conflicting results
strongest in infants. A randomized con- at CD4 .500 cells/mm3.48–51 Adult data
trolled trial (RCT) of HIV-infected infants further support earlier treatment to
Difference vs Severeb

in South Africa found that, compared enhance CD4 recovery52 and prevent
9.4 (6.7 to 12.0)
Mean (95% CI)

5.9 (2.9 to 9.0)

3.9 (0.8 to 7.0)
Reference

with delaying treatment until infants met HIV sexual transmission.53 Consequently,
prespecified clinical or CD4% criteria, DHHS guidelines recommend universal
immediate HAART initiation reduced early HAART in all HIV-infected adults and
Adjusteda

infant mortality by 76% and HIV pro- adolescents.44

gression by 75%.8 Infants with immediate From our PENPACT-1 results, we are
38.5 (36.5 to 40.4)
35.1 (32.8 to 37.3)
33.1 (30.6 to 35.5)
29.1 (27.3 to 31.0)
Mean (95% CI)

treatment had better gross motor and concerned by the poor outcomes in
CD4%

general neurodevelopmental scores,10 older children and adolescents, partic-

and treatment ,6 months old may ularly those with poor baseline immu-
have faster improvements in weight-for- nologic status. Biologically, we expected
age and head circumference-for-age relationships between CD4% recovery
Difference vs Severeb

11.0 (7.8 to 14.1)

z scores. 11 A Cochrane review on and age to plateau because thymic po-

Mean (95% CI)

6.3 (2.8 to 9.8)

3.1 (0.0 to 6.2)

d Wald upper 95% confidence limits exceeding 100% were rounded to 100%.
Reference

effectiveness of HAART in HIV-infected tential stabilizes as children approach

children ,3 years old concluded that adult immune maturity.24,27,28 Instead,
Unadjusted

immediate HAART reduces morbidity CD4% outcomes declined through ado-

and mortality in infants, but clinical lescence, likely from increasing ad-
benefits of universal treatment initia- herence struggles and viral failure.7,54
40.0 (37.4 to 42.6)
35.3 (32.3 to 38.4)
32.1 (29.6 to 34.7)
29.0 (27.3 to 30.8)
Mean (95% CI)

tion in children aged 1 to 3 years remain Consistent with child-specific pre-

CD4%

unclear.9 dictions,24 older children and adoles-

Unadjusted P , .001, adjusted P , .001.
c Unadjusted P , .001, adjusted P , .001.

Evidence for early treatment in children cents may benefit most dramatically
$1 year old is less compelling. An from earlier HAART initiation (comple-
RCT in Thailand and Cambodia of HIV- mentary to strategies for better case
Deficiency Classification
Baseline WHO Immune

infected children aged 1 to 12 years finding, adherence, or therapeutic

Advanced, n = 38

with CD4% 15% to 24% found that im- approaches for improving immuno-
Severe, n = 80
None, n = 37

logic potential).
Mild, n = 27

mediate versus delayed HAART resulted

in similar 144-week AIDS-free survival Immunologic benefits of earlier treatment
(98.7% vs 97.9%) but improved height should be weighed against potential
b
a

PEDIATRICS Volume 134, Number 4, October 2014 e1109

 precluded more intricate model speci-
fication. Finally, analysis of potential
sources of bias38 suggested possible
unmeasured confounding from host
immunology and HIV virulence, which
were untestable in our data.

CONCLUSIONS
Earlier HAART initiation in children with
vertically acquired HIV-1 substantially
improves immunologic recovery within
4 years. Optimizing treatment timing
by CD4% and age may have significant
long-term immunologic benefits. Older
children and adolescents, in particular,
may benefit from earlier treatment.
Nevertheless, immunologic benefits
diminished over time, and treatment
decisions should weigh potential
risks, including viral failure. Esti-
mates of this kind allow immunologic
benefits of alternative HAART initia-
tion thresholds to be balanced against
their clinical, social, and financial
costs.

ACKNOWLEDGMENTS

THE PENPACT-1 (PAEDIATRIC

EUROPEAN NETWORK FOR
TREATMENT OF AIDS [PENTA 9]/
PEDIATRIC AIDS CLINICAL TRIALS
GROUP [PACTG 390]) STUDY TEAM

FIGURE 2
PENPACT-1 Protocol Team
Cumulative proportion of children with CD4% recovery to normal versus weeks after HAART initiation, by PACTG/International Maternal Pediatric
age at HAART initiation (0–4, 5–9, 10–17 years). Primary outcome is CD4% $10th percentile for age by
week 192, marked by vertical dashed line. P value is from log-rank statistic. Adolescent AIDS Clinical Trials Group
(IMPAACT)/Eunice Kennedy Shriver Na-
tional Institute of Child Health and
harms. In PENPACT-1, viral failure was over time and viral failure risks high- Human Development (NICHD): P. Brouwers,
worse at age extremes, consistent with light the importance of long-term lon- D. Costello, E. Ferguson, S. Fiscus,
studies finding poor viral suppression gitudinal studies for understanding J. Hodge, M. Hughes, C. Jennings, A. Melvin
at younger ages6,19 and myriad adher- implications of different HAART strate- (Co-Chair), R. McKinney (Co-Chair),
ence difficulties in adolescents.7,54 For gies in children. L. Mofenson, M. Warshaw, M.E. Smith,
some children, immunologic recovery Our study was limited by including only S. Spector, E. Stiehm, M. Toye, R. Yogev.
is transient, and starting HAART earlier participants from a clinical trial in PENTA: J.P. Aboulker, A. Babiker, H. Castro,
may eventually lead to fewer treatment predominantly industrialized countries. A. Compagnucci, A. De Rossi, C. Giaquinto,
options. Fortunately, HAART initiation at Results may not generalize to other set- J. Darbyshire, M. Debré, D.M. Gibb,
higher CD4 counts may mitigate anti- tings. Low sample sizes in certain CD4% L. Harper, L. Harrison, N. Klein, D. Pillay,
retroviral resistance at viral failure.55 and age strata, particularly adolescents, Y. Saidi, G. Tudor-Williams (Co-Chair),
Still, diminishing immunologic benefits decreased precision of estimates and A.S. Walker.

e1110 YIN et al
 ARTICLE

FIGURE 3
Relationship between age at HAART initiation and (A) proportion of children with normal CD4% within 4 years, (B) CD4% at 4 years, (C) proportion of children with
normal CD4% at 4 years, (D) proportion of children with viral failure within 4 years. Panels A, B, and C illustrate splines; panel D illustrates a cubic function.

Data and Safety Monitoring Board: Austria: Universitätsklinik für Kinder Janeiro: R.H. Oliveira, M.C. Sapia, T. Abreu,
B. Brody, C. Hill, P. Lepage, J. Modlin, und Jugendheilkunde, Graz: B. Zöhrer, L. Evangelista, A. Pala, I. Fernandes,
A. Poziak, M. Rein (Chair 2002–2003), W. Zenz, E. Daghofer, K. Pfurtscheller, I. Farias, M. de F. Melo (L), H. Carreira (P),
M. Robb (Chair 2004–2009), T. Fleming, B. Pabst (L). L.M. Lira (P); Instituto de Infectologia
S. Vella, K.M. Kim. Bahamas: Princess Margaret Hospital: Emilio Ribas, São Paolo: M. Della Negra,
M.P. Gomez, P. McNeil, M. Jervis, I. Whyms, W. Queiroz, Y.C. Lian; D.P. Pacola; Fleury
Clinical Sites (L = laboratory, D. Kwolfe, S. Scott (P). Laboratories; Federal University of Minas
P = pharmacy) Brazil: University of São Paulo at Gerais, Belo Horizonte: J. Pinto, F. Ferreira,
Argentina: Hospital de Pediatria Dr Ribeirão Preto: M.M. Mussi-Pinhata, F. Kakehasi, L. Martins, A. Diniz, V. Lobato,
J.P. Garrahan, Buenos Aires: R. Bologna, M.L. Issac, M.C. Cervi, B.V.M. Negrini, M. Diniz, C. Hill (L), S. Cleto (L), S. Costa (P),
D. Mecikovsky, N. Pineda, L. Sen (L), T.C. Matsubara, C.B.S.S. de Souza (L), J. Romeiro (P).
A. Mangano (L), S. Marino (L), C. Galvez (L); J.C. Gabaldi (P); Institute of Pediatrics France: Hôpital d’enfants Armand
Laboratorio Fundai: G. Deluchi (L). (IPPMG), Federal University of Rio de Trousseau, Paris: C. Dollfus, M.D. Tabone,

PEDIATRICS Volume 134, Number 4, October 2014 e1111

TABLE 3 Projected Probabilities of Ever Recovering a Normal CD4% Within 4 Years, by WHO Immunodeficiency Classification and Agea,b
Baseline WHO Immune Age at HAART Initiation Overallc
Deficiency Classification n = 162
0 to ,1 y 1 to ,3 y 3 to ,5 y 5 to ,8 y 8 to ,13yr 13 to ,18 y % (95% CI)
n = 26 n = 19 n = 24 n = 38 n = 38 n = 17
% (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI)
Mild, n = 31 97 (88% to 100%) 96 (88% to 100%) 96 (87% to 100%) 95 (86% to 100%) 93 (82% to 100%) 91d (76% to 100%) 95 (86% to 100%)
Advanced, n = 40 95 (75% to 100%) 92 (74% to 100%) 86 (72% to 100%) 80 (68% to 92%) 70 (53% to 86%) 56 (27% to 85%) 80 (68% to 92%)
Severe, n = 91 83 (69% to 98%) 77 (65% to 90%) 69 (59% to 78%) 59 (50% to 68%) 44 (31% to 56%) 22 (0% to 44%) 59 (50% to 68%)
Overall,e n = 162 94 (83% to 100%) 88 (79% to 97%) 80 (73% to 86%) 70 (64% to 77%) 56 (46% to 65%) 35 (18% to 52%) 71 (65% to 77%)
a Additive Poisson regression estimates; adjusted for age, gender, race, and interaction between WHO Immunologic Classification and age; estimated at the covariate distribution of primary
outcome subset.
b Wald upper 95% confidence limits exceeding 100% were rounded to 100%.
c Overall WHO category estimates are at the primary endpoint subset mean age (6.3 y).
d n = 0 for this cell.
e Overall age estimates are adjusted for gender and race only.

M.F. Courcoux, G. Vaudre, A. Dehée (L), F. Damond (L), J. Leleu (L), D. Beniken Italy: Clinica Pediatrica, Ospedale
A .Schnuriger (L), N. Le Gueyades (P), (L), G. Alexandre-Castor (L). L. Sacco, Milan: V. Giacomet, A. Viganò,
C. De Bortoli (P); CHU Hôtel Dieu, Nantes: Germany: Universitäts-Kinderklinik I. Colombo, D. Trabattoni (L), A. Berzi (L);
F Méchinaud, V Reliquet, J. Arias (L), Düsseldorf: J. Neubert, T. Niehues, Clinica Pediatrica, Università di Brescia:
A. Rodallec (L), E. André (L), I. Falconi (P), H.J. Laws, K. Huck, S. Gudowius, R. Badolato, F. Schumacher, V. Bennato,
A. Le Pelletier (P); Hôpital de l’Archet II, K. Siepermann, H. Loeffler, S. Bellert (L), M. Brusati, A. Sorlini, E. Spinelli,
Nice, F. Monpoux, J. Cottalorda (L), A. Ortwin (L); Universitäts-Kinderkliniken, M. Filisetti, C. Bertulli; Clinica Pediatrica,
S. Mellul (L); Hôpital Jean Verdier, Munich: G. Notheis, U. Wintergerst, Università di Padova: O. Rampon,
Bondy: E. Lachassinne; Laboratoire F. Hoffman, A. Werthmann, S. Seyboldt, C. Giaquinto, M. Zanchetta (L); Ospedale
de virologie-Hôpital Necker Enfants L. Schneider, B. Bucholz; Charité-Medizische S. Chiara, Trento: A. Mazza, G. Stringari,
Malades, Paris: J. Galimand (L), Fakultät der Humboldt—Universitätzu G. Rossetti (L); Ospedale del Bambino
C. Rouzioux (L), M.L. Chaix (L), Z. Benabadji Berlin: C. Feiterna-Sperling, C. Peiser, Gesù, Rome: S. Bernardi, A. Martino,
(P), M. Pourrat (P); Hôpital Cochin R. Nickel, T. Schmitz, T. Piening, C. Müller G. Castelli Gattinara, P. Palma, G. Pontrelli,
Port-Royal-Saint Vincent de Paul, Paris: (L); Kinder und Jugendklinik, Universität H. Tchidjou, A. Furcas, C. Frillici, A. Mazzei,
G. Firtion, D. Rivaux, M. Denon, N. Boudjoudi, Rostock: G. Warncke, M. Wigger, A. Zoccano (P), C. Concato (L).
F. Nganzali, A. Krivine (L), J.F. Méritet (L), R. Neubauer. Romania: Spitalul Clinic de Boli Infectioase
G. Delommois (L), C. Norgeux (L), C. Guérin Ireland: Our Lady’s Children’s Hospital Victor Babes, Bucharest: D Duiculescu,
(P); Hôpital Louis Mourier, Colombes: Crumlin, Dublin: K. Butler, A.L. Chong, C Oprea, G Tardei (L), F Abaab (P); Institutul
C. Floch, L. Marty, H. Hichou (L), T. Boulger, A. Menon, M. O’Connell, de Boli Infectioase Matei Bals, Bucharest:
V. Tournier (P); Hôpital Robert Debré, L. Barrett, A. Rochford, M. Goode, M Mardarescu, R Draghicenoiu, D Otelea
Paris: A. Faye, I. Le Moal, M. Sellier (P), E. Hayes, S. McDonagh, A. Walsh, A. Doyle, (L), L Alecsandru (P); Clinic Municipal,
L. Dehache (P); Laboratoire de virologie, J. Fanning (P), M. O’Connor (P), M. Byrne Constanta: R Matusa, S Rugina, M Ilie, Silvia
Hôpital Bichat Claude Bernard, Paris: (L), N. O’Sullivan (L), E. Hyland (L). Netescu (P). Clinical monitors: C Florea,

TABLE 4 Projected Probabilities of Having a Normal CD4% at 4 Years, by WHO Immunodeficiency Classification and Agea,b
Baseline WHO Immune Age at HAART Initiationc Overallc
Deficiency Classification n = 182
0 to ,1 y 1 to ,3 y 3 to ,5 y 5 to ,8 y 8 to ,13 y 13 to ,18 y % (95% CI)
n = 35 n = 25 n = 25 n = 45 n = 38 n = 14
% (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI)
None, n = 37 99 (88% to 100%) 97 (87% to 100%) 93 (85% to 100%) 89 (80% to 98%) 83 (70% to 96%) 74 (53% to 96%) 90 (81% to 99%)
Mild, n = 27 86 (67% to 100%) 83 (65% to 100%) 80 (63% to 97%) 76 (59% to 93%) 70 (51% to 89%) 61d (36% to 86%) 77 (60% to 94%)
Advanced, n = 38 74 (55% to 94%) 72 (54% to 90%) 69 (52% to 85%) 65 (49% to 80%) 59 (42% to 75%) 50 (28% to 71%) 66 (50% to 81%)
Severe, n = 80 56 (41% to 70%) 53 (41% to 66%) 50 (39% to 61%) 46 (35% to 57%) 40 (27% to 53%) 31 (11% to 52%) 47 (36% to 58%)
Overall,e n = 182 75 (64% to 85%) 72 (63% to 81%) 68 (60% to 75%) 63 (56% to 70%) 56 (45% to 66%) 45 (27% to 63%) 64 (58% to 71%)
a Additive Poisson regression estimates; adjusted for age, gender, and race; estimated at covariate distribution of secondary outcomes subset.
b Wald upper 95% confidence limits exceeding 100% were rounded to 100%.
c Overall WHO category estimates are at the secondary end point subset mean age (5.8 y).
d n = 0 for this cell.
e Overall age estimates are adjusted for gender and race only.

e1112 YIN et al
 ARTICLE

E Voicu, D Poalelungi, C Belmega, LVladau, Health, London: M. Jacobsen (L); John versity of Miami (L); University College of
A Chiriac. Radcliffe Hospital, Oxford: S. Segal, Florida College of Medicine—Gainesville:
Spain: Hospital Materno-Infantil 12 de A. Pollard, D. Kelly, S. Yeadon, B. Ohene-Kena R. Lawrence; University of Rochester Pe-
Octubre, Madrid: J.T. Ramos Amador, Y. Peng (L), T. Dong (L), Y. Peng (L), K. Jeffries diatrics: G.A. Weinberg, B. Murante,
M.I. Gonzalez Tomé, P. Rojo Conejo, (L), M. Snelling (P), Nottingham University S. Laverty; Miller Children’s Hospital
M. Fernandez, R. Delgado Garcia (L), Hospitals: A. Smyth, J. Smith; Chelsea and Long Beach: A. Deveikis, J. Batra, T. Chen,
J.M. Ferrari (P); Institute de Salud Westminster Hospital, London: B. Ward; D. Michalik, J. Deville, K. Elkins, S. Marks,
Carlos III, Madrid: M. Garcia Lopez, Mortimer Market Centre, London: J. Jackson Alvarez, J. Palm, I. Fineanganofo
M.J. Mellado Peña, P. Martin Fontelos, E. Jungmann; Doncaster Royal Infirmary: (L), M. Keuth (L), L. Deveikis (L),
I. Jimenez Nacher (P); Biobanco Gregorio C. Ryan, K. Swaby; Health Protection Agency, W. Tomosada (P); Tulane University
Marañon, Madrid: M.A. Muñoz Fernandez London: A. Buckton (L); Health Protection New Orleans: R. Van Dyke, T. Alchediak,
(L), J.L. Jimenez (L), A. García Torre (L); Agency, Birmingham: E. Smit (L). M. Silio, C. Borne, S. Bradford, S. Eloby-
clinical monitors: M. Penin, R. Pineiro United States: Harlem Hospital Center: Childress (L), K. Nguyen (P); University
Perez, I. Garcia Mellado. E.J. Abrams, S. Champion, A.D. Fernandez, of Florida/Jacksonville: M.H. Rathore,
D. Calo, L. Garrovillo, K. Swaminathan, A. Alvarez; A. Mirza, S. Mahmoudi,
United Kingdom: Bristol Royal Chil-
T. Alford, M. Frere, Columbia University M. Burke; University of Puerto Rico:
dren’s Hospital: A. Finn, M. LaJeunesse,
Laboratories, J. Navarra (P, Town Total I.L. Febo, L. Lugo, R. Santos; Children’s
E. Hutchison, J. Usher (L), L. Ball (P),
Health); New York University School of Hospital Los Angeles: J.A. Church,
M. Dunn (P); St George’s Healthcare NHS
Medicine: W. Borkowsky, S. Deygoo, T. Dunaway, C. Rodier; St Jude/University
Trust, London: M. Sharland, K. Doerholt,
T. Hastings, S. Akleh, T. Ilmet (L); Seattle of Tennessee Health Science Center:
S. Storey, S. Donaghy, R. Chakraborty,
Children’s Hospital: A. Melvin, K. Mohan, P. Flynn, N. Patel, S. DiScenza, M. Donohoe;
C. Wells (P), K. Buckberry (P), P. Rice (P);
G. Bowen (additional support by National Western New England Maternal Pediatric
University Hospital of North Staffordshire:
Institutes of Health grant UL1 RR025014); Adolescent AIDS: K. Luzuriaga, D. Picard;
P. McMaster, P. Butler, C. Farmer (L),
University of South Florida: P.J. Emmanuel, Texas Children’s Hospital: M. Kline,
J. Shenton (P), H. Haley (P), J. Orendi (L),
J. Lujan-Zimmerman, C. Rodriguez, M.E. Paul, W.T. Shearer, C. McMullen-
University Hospital Lewisham: J. Stroobant,
S. Johnson, A. Marion, C. Graisbery, Jackson; Children’s Memorial Hos-
L. Navarante, P. Archer, C. Mazhude, D. Scott,
D. Casey, G. Lewis; All Children’s Hos- pital, Chicago: R. Yogev, E. Chadwick,
R. O’Connell, J. Wong (L), G. Boddy (P);
pital Laboratories; Oregon Health and E. Cagwin, K. Kabat; New Jersey Medical
Sheffield Children’s Hospital: F. Shackley,
Science University: J. Guzman-Cottrill, School: A. Dieudonne, P. Palumbo,
R. Lakshman, J. Hobbs, G. Ball (L),
R. Croteau; San Juan City Hospital: J. Johnson; Robert Wood Johnson Medi-
G. Kudesia (L), J. Bane (P), D. Painter (P);
M. Acevedo-Flores, M. Gonzalez, L. Angeli; cal School, New Brunswick: S. Gaur,
Ealing Hospital NHS Trust: K. Sloper,
L. Fabregas, Laboratory 053, P Valentin L. Cerracchio; Columbia IMPAACT: M. Foca,
V. Shah, A. Cheng (P), A. Aali (L); King’s
(P); State University of New York A. Jurgrau, S. Vasquez Bonilla, G. Silva;
College Hospital, London: C. Ball, S. Hawkins,
(SUNY) Upstate Medical University, Babies’ Hospital, Columbia/Presbyterian
D. Nayagam, A. Waters, S. Doshi (P); Newham
Syracuse: L. Weiner, K.A. Contello, Medical Center, New York: A. Gershon;
University Hospital: S. Liebeschuetz,
W. Holz, M. Butler; SUNY, Health Science University of Massachusetts Medical
B. Sodiende, D. Shingadia, S. Wong,
Center at Stonybrook: S. Nachman, Center, Worcester: J. Sullivan; University
J. Swan (P), Z. Shah (P); Royal Devon and
M.A. Kelly, D.M. Ferraro, University of of California—Los Angeles Medical
Exeter Hospital: A. Collinson, C. Hayes,
North Carolina Retrovirology Labora- Center: Y. Bryson; Children’s Hospital,
J. King (L), K. O’Connor (L); Imperial
College Healthcare NHS Trust, London: tory; Howard University Hospital: Seattle: L. Frenkel; University of North
S. Rana, C. Reed, E. Yeagley, A. Malheiro, Carolina—Chapel Hill Virology Labora-
G. Tudor-Williams, H. Lyall, K. Fidler,
J. Roa; Los Angeles County and Univer- tory: S. Fiscus (L), J. Nelson (L).
S. Walters, C. Foster, D. Hamadache,
C. Newbould, C. Monrose, S. Campbell, sity of Southern California Medical
Trials Units/Support
S. Yeung, J. Cohen, N. Martinez-Allier, Center: M. Neely, A. Kovacs, L. Spencer,
D. Melvin, J. Dodge, S. Welch, G. Tatum, J. Homans, Y. Rodriguez Lozano, Mater- INSERM SC10 Paris: J.P. Aboulker,
A. Gordon, S. Kaye (L), D. Muir (L), D. Patel nal Child Virology Research Laboratory, A. Compagnucci, G. Hadjou, S. Léonardo,
(P); Great Ormond Street Hospital: V. Novelli, Investigational Drug Service; South Y. Riault, Y. Saïdi.
D. Gibb, D. Shingadia, K. Moshal, J. Lambert, Florida Children’s Diagnostic & Treat- Medical Research Council Clinical Trials
N. Klein, J. Flynn, L. Farrelly, M. Clapson, ment Center: A. Puga, G. Talero, R. Sellers; Unit, United Kingdom: A. Babiker, L. Buck,
L. Spencer, M. Depala (P); Institute of Child Broward General Medical Center, Uni- J.H. Darbyshire, L. Farrelly, S. Forcat,

PEDIATRICS Volume 134, Number 4, October 2014 e1113

D.M. Gibb, H. Castro, L. Harper, L. Harrison, S. Bernardi, S. Blanche, A.B. Bohlin, G. Tudor-Williams, A.S. Walker, S. Welch,
J. Horton, D. Johnson, S. Moore, C. Taylor, R. Bologna, D. Burger, K. Butler, U. Wintergerst, N. Valerius.
A.S. Walker. G. Castelli-Gattinara, H. Castro, P. Clayden,
Westat/NICHD: D. Collins, S. Buskirk, A. Compagnucci, J.H. Darbyshire, Additional Contributors
P. Kamara, C. Nesel, M. Johnson, M. Debré, R. De Groot, M. Della Negra, Methodological advice was provided by
A. Ferreira. A. De Rossi, A. Di Biagio, D. Duiculescu, C. Poole and S.R. Cole, University of
A. Faye, V. Giacomet, C. Giaquinto North Carolina—Chapel Hill. Manuscript
Frontier Science: J. Hodge, J. Tutko,
(Chair), D.M. Gibb, I. Grosch-Wörner, proofreading and suggestions were pro-
H. Sprenger.
M. Hainault, L. Harper, N. Klein, M. Lallemant, vided by R.J. McCulloh, Children’s Mercy
IMPAACT: M. Hughes, M. Warshaw, Hospitals and Clinics, University of
J. Levy, H. Lyall, M. Marczynska,
P. Britto, C. Powell. Missouri—Kansas City.
M. Mardarescu, M.J. Mellado Pena,
National Institute of Allergy and In- D. Nadal, L. Naver, T. Niehues, C. Peckham,
fectious Diseases: R. DerSimonian, D. Pillay, J. Popieska, J.T. Ramos Amador, Participants, Families, Staff
E. Handelsman (deceased). L. Rosado, R. Rosso (deceased), C. Rudin, We thank all the children, families, and
PENTA Steering Committee: J.P. Aboulker, Y. Saïdi, H. Scherpbier, M. Sharland, staff from the centers participating in
J. Ananworanich, A. Babiker, E. Belfrage, M. Stevanovic, C. Thorne, P.A. Tovo, the PENPACT-1 trial.

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Dr Yin conceptualized the study aims, designed the analytical plan, conducted all data analyses, interpreted the results, and drafted and revised the manuscript;
Ms Warshaw contributed to development of the study aims, guided the analytical plan, guided and supervised data analysis, contributed to results interpretation,
and reviewed and revised the manuscript; Dr Miller guided the analytical plan, guided data analyses, contributed to results interpretation, and reviewed and
revised the manuscript; Ms Castro, Ms Harper, Dr Klein, and Dr Lewis contributed to interpretation of results and reviewed and revised the manuscript; Dr. Fiscus
conducted laboratory analysis of specimens and reviewed and revised the manuscript; Ms Harrison contributed to the analytical plan, contributed to
interpretation of results, and reviewed and revised the manuscript; Dr Melvin was Pediatric AIDS Clinical Trials Group co-chair of the study, contributed to
development of study aims, acquired data, and reviewed the manuscript; Dr Tudor-Williams was Paediatric European Network for Treatment of AIDS co-chair of the
study, contributed to development of study aims, acquired data, and reviewed and revised the manuscript; Dr McKinney was Pediatric AIDS Clinical Trials Group co-
chair of the study, contributed to development of study aims and analytical plan, acquired data, guided data analysis, interpreted results, and reviewed and revised
the manuscript; and all authors approved the final manuscript as submitted.
Clinical Trial Registration: This trial has been registered with www.isrctn.org (ISRCTN73318385).
www.pediatrics.org/cgi/doi/10.1542/peds.2014-0527
doi:10.1542/peds.2014-0527
Accepted for publication Jul 24, 2014
Address correspondence to Dwight E. Yin, MD, MPH, Division of Infectious Diseases, Department of Pediatrics, Children’s Mercy Hospitals and Clinics, 2401 Gillham
Rd, Kansas City, MO 64108. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2014 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr McKinney serves on an advisory board for Janssen Pharmaceuticals; the other authors have indicated they have no financial
relationships relevant to this article to disclose.
FUNDING: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) training grants to the Department of
Pediatrics, Duke University Medical Center (T32 HD043029) and the Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center (T32 HD060558).
The PENPACT-1 trial was sponsored jointly by the Paediatric European Network for Treatment of AIDS (PENTA) Foundation, AgènceNationale de Recherchesur le Sidaet les
hepatitis virales (ANRS), and the Pediatric AIDS Clinical Trials Group (PACTG), subsequently named the International Maternal Pediatric Adolescent AIDS Clinical Trials Group
(IMPAACT). Overall support for PACTG/IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI068632), the NICHD, and the National
Institute of Mental Health (AI068632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of
Health. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases
cooperative agreement 5 U01 AI41110 with the PACTG and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and
Infectious Diseases and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/
HHSN267200800001C). PENTA is a coordinated action of the European Commission/European Union, supported by the seventh framework programme (FP7/2007-2013) under
the Eurocoord grant agreement 260694, the sixth framework contract LSHP-CT-2006-018865, the fifth framework programme contract QLK2-CT-2000-00150, and by the PENTA
Foundation. UK clinical sites were supported by a grant from the Medical Research Council (MRC); those in Italy by a grant from the Istituto Superiore di Sanita—Progetto
Terapia Antivirale 2004, 2005. GlaxoSmithKline and Bristol-Myers Squibb provided drugs in Romania. The trial was coordinated by 4 trials centers: the MRC Clinical Trials Unit,
London, United Kingdom (with support from the MRC); INSERM SC10, Paris, France (supported by ANRS); Frontier Science, New York, NY; and Westat, Rockville, MD (supported
by NICHD). Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: Dr McKinney is a member of several Data Safety Monitoring Boards for Gilead Sciences. The authors have indicated they have
no potential conflicts of interest to disclose.

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